BRAIN CRF AND NOREPINEPHRINE AND STRESS

压力可能是一个重要因素， 精神疾病应激刺激激活儿茶酚胺能系统 (the交感神经系统、肾上腺髓质和大脑 下丘脑-垂体-肾上腺皮质（HPA） 轴线这些系统被认为是互补的，但关系 他们之间的关系是很难理解的。有大量证据表明， HPA轴异常的抑郁症和焦虑症，但 目前的治疗强调使用对去甲肾上腺素能有活性的药物， 能和GABA能系统。 我们和其他人已经证明，脑内注射 促肾上腺皮质激素释放因子（CRF）可以模拟许多内分泌， 观察到自主神经、神经化学和焦虑样行为反应 压力很大大脑CRF可能是其中一些的介导者 反应是由脑内应用的能力， CRF拮抗剂，以防止或减弱它们。我们以往的研究 提示CRF和去甲肾上腺素能活性在应激相关的 不同行为模式的行为变化： 小鼠的多室，以及防御性戒断和冻结 大鼠的行为。这些与压力有关的药物的药理学分析 这些变化表明，它们可能是通过激活 去甲肾上腺素能神经元反过来激活CRF细胞， α 1受体然而，独立的神经化学和 电生理学证据表明，CRF给药可 激活去甲肾上腺素能神经元。因此，CRF和 脑中的去甲肾上腺素能系统可能相当复杂。 拟议的实验将检查CRF之间的关系- 含有去甲肾上腺素能神经元。我们的假设是 下丘脑外CRF通过调节NE影响焦虑样行为 蓝斑水平的活动。具体目标包括 确定CRF可以引起行为的大脑部位， 类似于在压力下观察到的反应。然后我们将研究 这些部位注射CRF对去甲肾上腺素释放的影响 通过体内微透析和体内伏安法评估。CRF 拮抗剂将在相同的研究中心进行测试，以确定其 拮抗行为和神经化学反应， 对约束和CRF的反应。重点会放在蓝斑上 (LC)因为这种结构与压力和焦虑有关 应答中央杏仁核接收来自LC的输入， 在获得和表达恐惧和焦虑方面起着作用， 第二个注意力中心。如果大量的CRF-NE相互作用 大脑去甲肾上腺素能系统的已建立的选择性损伤将 用于识别参与行为的神经回路， 对克制和CRF的反应。这些实验应该可以帮助我们 了解CRF和去甲肾上腺素能之间的功能关系 神经元参与在压力下观察到的行为反应。 这种理解可能对治疗 抑郁症和焦虑症。

Stress can be an important factor precipitating and exacerbating in mental illness. Stressful stimuli activate catecholaminergic systems (the sympathetic nervous system, the adrenal medulla, and cerebral catecholamines), and the hypothalamo-pituitary-adrenocortical (HPA) axis. These systems are regarded as complementary, but the relationships between them are poorly understood. There is substantial evidence for abnormalities of the HPA axis in major depression and anxiety, but current treatments emphasize the use of drugs active on noradrenergic, serotonergic and GABAergic systems. We and others have demonstrated that intracerebral injections of corticotropin-releasing factor (CRF) can mimic many of the endocrine, autonomic, neurochemical and anxiety-like behavioral responses observed in stress. That cerebral CRF may be a mediator of some of these responses is suggested by the ability of intracerebral application of CRF antagonists to prevent or attenuate them. Our previous studies have implicated both CRF and noradrenergic activity in the stress-related behavioral changes in different behavioral paradigms: the multicompartment chamber in mice, and defensive withdrawal and freezing behavior in rats. Pharmacological analyses of these stress-related changes suggests that they may be mediated by activation of noradrenergic neurons which in turn activate CRF-containing cells via alpha1-receptors. However, independent neurochemical and electrophysiological evidence indicates that CRF administration can activate noradrenergic neurons. Thus, the relationships between CRF and noradrenergic systems in the brain may be considerably more complex. The proposed experiments will examine the relationships between CRF- containing and noradrenergic neurons. Our working hypothesis is that extrahypothalamic CRF affects anxiety-like behavior by modulating NE activity a the level of the locus coeruleus. Specific objectives include the identification of the brain sites in which CRF can elicit behavioral responses resembling those observed in stress. We will then study the effects of CRF injected into these sites on norepinephrine release assessed by in vivo microdialysis and in vivo voltammetry. CRF antagonists will be tested in the same sites for their ability to antagonize the behavioral and neurochemical responses observed in response to restraint and CRF. The focus will be on the locus coeruleus (LC) because this structure has been implicated in stress and anxiety responses. The central amygdala that receives input from the LC and plays a role in acquiring and expression of fear and anxiety will be the second center of attention. If substantial CRF-NE interactions are established, selective lesions of cerebral noradrenergic systems will be used to identify neuronal circuits involved in the behavioral responses to restraint and CRF. These experiments should help us to understand the functional relationships between CRF and noradrenergic neurons involved in the behavioral responses observed during stress. Such an understanding may have implications for the treatment of depression and anxiety disorders.